Syk is a non-receptor tyrosine kinase that is involved in coupling activated immunoreceptors to signal downstream events that mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis. Syk is widely expressed in hematopoietic cells. Syk inhibitors have potential anti-inflammatory and immunomodulating activities. They inhibit Syk-mediated IgG Fc epsilon and gamma receptor and BCR receptor signalling, resulting in inhibition of the activation of mast cells, macrophages, and B-cells and related inflammatory responses and tissue damage. Mast cells play a major role in type I hypersensitivity reactions and have been implicated in urticaria, bronchial asthma, anaphylaxis and other allergic conditions. Accordingly, Syk inhibitors have attracted interest in a number of therapeutic areas, including the treatment of rheumatoid arthritis, B-cell lymphoma, asthma, rhinitis and cutaneous disorders such as acute and chronic urticaria, mastocytosis, cutaneous lupus, atopic dermatitis, autoimmune bullous conditions including pemphigus and pemphigoid and other mast cell mediated diseases of the skin.
Acute and chronic urticaria are common skin diseases thought to affect around 25% of the total population within the USA. Although urticaria can be triggered by allergic reactions many cases have an unclear etiology. Chronic urticaria is defined as when wide spread wheals are present for greater than 6 weeks. There are many pathological similarities in chronic urticaria patients, in terms of extent of wheals in the skin, with allergen-induced mast and basophil cell degranulation reactions via IgE activation. Around 40% of chronic urticaria patients contain serum IgG auto-antibodies targeting IgE or the IgE receptor (Fc Epsilon Receptor) and these are thought to drive the histamine and other mediator release via mast and basophil degranulation. Syk inhibitors would inhibit the signalling response post IgE mediated Fc Epsilon activation and inhibit the mediator release known to be involved in chronic pruritis in multiple diseases.
Cutaneous mastocytosis is defined as an excessive accumulation of mast cells in the skin normally seen in both the paediatric and adult population. It is a rare disease thought to be due to a dysregulation in the proliferative capacity of the mast cells. The excessive production of mast cells in the skin leads to an increased release of cytokines and histamines which lead to itching, skin lesions, and in some cases where there is a systemic involvement, anaphylactic shock or low blood pressure.
Cutaneous lupus is a condition of the skin found in some patients with a discoid form of lupus erythematosus. The disorder is characterised by a red raised rash on the face or scalp and other areas of the body and mast cells and antibody deposition are known to be involved in the lesions.
A Syk inhibitor applied topically would decrease the production of cytokines, histamines and other mediators potentially leading to reduced itching and inflammatory infiltration in the skin.
Atopic dermatitis is a very common and sometimes long lasting inflammatory skin disorder characterised by redness and pruritis. The disease often occurs with other allergic conditions such as hay fever or asthma, is found predominantly in young children and is exacerbated by contact with allergens. Mast cell involvement is understood to lead to the characteristic itching and excessive scratching which can lead to an increase in bacterial infections in the skin. Topical application of a Syk inhibitor could reduce these symptoms.
Autoimmune bullous conditions including pemphigus and pemphigoid are acute and chronic skin diseases involving the formation of blisters. Bullous pemphigoid (BP) is a chronic, autoimmune, subepidermal, blistering skin disorder (unlike pemphigus where the blistering is intraepidermal). These rare diseases generally affect people over the age of 70. Autoantibodies are generated against the basement membrane layer of the skin leading to activation of complement and other inflammatory mediators. The inflammatory process initiates a release of enzymes which degrade proteins in the hemidesmosomal layers eventually leading to blisters as the layers of the skin fall apart. An urticarial rash and pruritis generally occur prior to onset of the blisters, so inhibition of mast cell degranulation and cytokine production post IgG antibody activation in macrophages with a Syk inhibitor could be beneficial in these diseases.
Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of the population. It is characterised by inflammation of articular joints leading to debilitating destruction of bone and cartilage. Recent clinical studies with rituximab, which causes a reversible B cell depletion, (J. C. W. Edwards et al. 2004, New Eng. J. Med. 350: 2572-2581), have shown that targeting B cell function is an appropriate therapeutic strategy in autoimmune diseases such as RA. Clinical benefit correlates with a reduction in auto-reactive antibodies (or rheumatoid Ffactor) and these studies suggest that B cell function and indeed auto-antibody production are central to the ongoing pathology in the disease
Studies using cells from mice deficient in Syk have demonstrated a non-redundant role of this kinase in B cell function. The deficiency in Syk is characterised by a block in B cell development (M. Turner et al 1995 Nature 379: 298-302 and Cheng et al 1995, Nature 378: 303-306). These studies, along with studies on mature B cells deficient in Syk (Kurasaki et al 2000, Immunol. Rev. 176:19-29), demonstrate that Syk is required for the differentiation and activation of B cells. Hence, inhibition of Syk in RA patients is likely to block B cell function and hence reduce rheumatoid factor production. In addition to the role of Syk in B cell function, of relevance to the treatment of RA, is the requirement for Syk activity in Fc receptor (FcR) signalling. FcR activation by immune complexes in RA has been suggested to contribute to the release of multiple pro-inflammatory mediators.
The contribution of Syk dependent processes to the pathology of RA has been reviewed by Wong et al (2004, ibid).
The results of a 12 week proof of concept clinical trial for the Syk inhibitor R788 (fostamatinib disodium, Rigel) have been published: Treatment of rheumatoid arthritis with a Syk inhibitor: A twelve-week, randomized, placebo-controlled trial, Arthritis & Rheumatis, 58(11), 2008, 3309-3318.
Syk inhibitors may also be useful in cancer therapy, specifically heme malignancies, particularly Non-Hodgkin's Lymphomas including follicular (FL), mantle cell, Burkitt and diffuse large B cell (DLBCL) lymphomas.
Studies have shown that Syk is dysregulated by overexpression and/or constitutively activation in a variety of primary B-lymphoma tumours and also in B-lymphoma cell lines. Syk, through the PI3K/AKT pathway, the PLD pathway and AKT independent signalling, activates mTOR (mammalian target of rapamycin) which in turn increases B-cell survival and proliferation. Inhibition of Syk in vitro, results in decreased mTOR activation and a reduction of clonicity in FL cells. Inhibition of Syk with curcumin in a murine model of B lymphoma (BKS-2) gave a significant reduction of tumour burden as measured by the total splenocyte number. (Leseux L. et al. Blood 15 Dec. 2006, Vol 108, No 13 pp 4156-4162 and Gururajan M. et al. Journal of Immunology, 2007, 178 pp 111-121).
Results of a Phase 2 clinical trial of R788 (fostamatinib disodium) in patients with relapsed or refractory B-Cell non-Hodgkin's lymphoma (NHL) show that the compound is well-tolerated by these patients, as well as a therapeutic benefit in patients suffering from diffuse large B-Cell lymphoma (DLBCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Despite the fact that the patients enrolled in this trial had advanced disease and had failed treatment with marketed therapies, a significant number of them were particularly responsive to Syk inhibition with R788 (Chen et al. Blood 2008 Vol 111 pp 2230-2237, www.Rigel.com)
Syk inhibitors may also be useful in the treatment of asthma and allergic rhinitis as they are important in transducing the downstream cellular signals associated with cross-linking FcεR1 and or FcγR1 receptors, and Syk is positioned early in the signalling cascade. In mast cells, for example, the early sequence of FcεR1 signalling following allergen cross-linking of receptor-IgE complexes involves first Lyn (a Src family tyrosine kinase) and then Syk.
Allergic rhinitis and asthma are diseases associated with hypersensitivity reactions and inflammatory events involving a multitude of cell types including mast cells, eosinophils, T cells and dendritic cells. Following exposure to allergen, high affinity immunoglobulin receptors for IgE (FcεRI) and IgG (FcγRI) become cross-linked and activate downstream processes in mast cells and other cell types leading to the release of pro-inflammatory mediators and airway spasmogens. In the mast cell, for example, IgE receptor cross-linking by allergen leads to release of mediators including histamine from pre-formed granules, as well as the synthesis and release of newly synthesised lipid mediators including prostaglandins and leukotrienes.
The Syk inhibitor R112 (Rigel), dosed intranasally in a phase I/II study for the treatment of allergic rhinitis, was shown to give a statistically significant decrease in PGD2, a key immune mediator that is highly correlated with improvements in allergic rhinorrhea, as well as being safe across a range of indicators, thus providing the first evidence for the clinical safety and efficacy of a topical Syk inhibitor (see Meltzer, Eli O.; Berkowitz, Robert B.; Grossbard, Elliott B. An intranasal Syk inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. Journal of Allergy and Clinical Immunology (2005), 115(4), 791-796). In a further phase II clinical trial, for allergic rhinitis, R112 was however shown as having a lack of efficacy versus placebo (Clinical Trials.gov Identifier NCT0015089).
WO 03/057695 (Boehringer Ingelheim Pharmaceuticals, Inc) describes 1,6 Naphthyridines that have Syk inhibitory activity. These are further described in “Discovery and SAR of Novel [1,6] Naphthyridines as Potent Inhibitors of Spleen Tyrosine Kinase (SYK) (Bioorganic & Medicinal Chemistry Letters 13 (2003) 1415-1418). This has been followed with two more recent patent applications, WO 2010/015518 and WO 2010/015529 (Boehringer Ingelheim Pharmaceuticals, Inc), describing 4-dimethylamino-phenyl-substituted naphthyridines and substituted naphthyridines, respectively.
WO 04/035604 discloses the structural co-ordinates of the human Syk protein.
There remains however the need to identify further compounds which are inhibitors of Syk.